A p38 MAPK-MEF2C pathway regulates B-cell proliferation.
B lymphocytes are an integral part of the adaptive immune system. On antigen binding to the B-cell receptor (BCR), B cells rapidly proliferate and differentiate into antibody-secreting plasma cells. The p38 mitogen-activated protein kinase (MAPK) pathway functions downstream of the BCR to control cell proliferation, but the transcriptional effectors of this pathway in B cells have remained elusive. In the present study, we inactivated Mef2c exclusively in B cells by conditional gene targeting in mice. Loss of MEF2C function resulted in a reduced immune response to antigen, defective germinal center formation, and a severe defect in B-cell proliferation, and we show that MEF2C regulates proliferation in response to BCR stimulation via the p38 MAPK pathway. p38 directly phosphorylates MEF2C via three residues in the C-terminal transactivation domain, establishing MEF2C as a direct transcriptional effector of BCR signaling via p38 MAPK.
Khiem
Dustin
D
Cardiovascular Research Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517, USA.
Cyster
Jason G
JG
Schwarz
John J
JJ
Black
Brian L
BL
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D011947:Receptors, Antigen, B-Cell; D048051:p38 Mitogen-Activated Protein Kinases